April

Study reveals bias in X-chromosome balancing act

X chromosome-inactivation ­– a crucial genetic balancing mechanism that occurs in all females – is not as balanced as previously thought, with a new study adding further evidence to the case.

Researchers from the Institute of Psychiatry and colleagues found evidence that gene inactivation is often skewed toward one X chromosome over the other, and that this bias may already be established in early childhood. The findings add to our understanding of the factors influencing sex differences, and how that may affect complex diseases.

Despite the overall high similarity in X chromosome inactivation patterns in identical twins at both ages 5 and 10 years, some identical twin-pairs had noticeably different patterns. This adds to the growing body of evidence showing how genetically identical individuals can be different in the way their genes are expressed. The differences in X chromosome inactivation between genetically identical twins highlight the potential relevance of skewed X chromosome inactivation for studies of the cause of disease.

While males have one X and one Y chromosome, females have two X chromosomes – one inherited from the father and one from the mother. To compensate for the duplication, genes are inactivated on one chromosome or the other in the early development of the embryo. This way, only one set of genes from either chromosome is working at any time.

For years, scientists thought that the level of inactivation across cells was split 50:50 between both chromosomes, with genes on either chromosome standing an equal chance of being inactivated. However, recent studies have suggested that the process may not be as equal as previously thought.

The new study is the first to look at the pattern of X chromosome-inactivation in young children over a period of time. The researchers followed 23 pairs of identical and 22 pairs of non-identical twin girls, taking DNA samples from their cheek cells at the ages of 5 and 10.

By the age of 5 there was already evidence of a bias in X chromosome-inactivation. In 12 per cent of all children the researchers found skewing of greater than 20 per cent toward the silencing of one X chromosome over the other. This effect became more pronounced over time, being seen in 17 per cent of all children aged 10. The direction of the bias – toward silencing either the maternal or paternal chromosome – remained the same over time.

The researchers also found a greater similarity in results between identical twins (which develop from the same embryo) compared with non-identical twins (who develop from two separate embryos). This was greater than one would expect if X chromosome-inactivation were indeed as random as previously thought. The findings suggest that bias in the process may already be established very early in development – even before the point at which an embryo splits to form identical twins.

‘Our data not only provide insight into the factors behind skewed X chromosome inactivation in young female children, but also demonstrate the lability of this pattern in early childhood’ said Chloe Wong, a PhD student in the SGDP’s Psychiatric Epigenetics group, and one of the authors of the study.